Vonoprazan-associated nephrotoxicity: extensive real-world evidence from spontaneous adverse drug reaction reports
Authors: Masayuki Ishida, Masami Tsuchiya, Junko Naito, Hitoshi Kawazoe, Daichi Watanabe, Yujiro Nonaka, Mika Sano, Hiroyasu Sakai, Akio Suzuki, Keisuke Kumada, Hiroyuki Okura, Masahito Shimizu, Hirotoshi Iihara
Journal: Kidney International (2022)

Vonoprazan, a potassium-competitive acid blocker possessing a new mechanism of action, was first approved in Japan in 2015 for the treatment of acid-related diseases. Vonoprazan inhibits acid secretion in the cells of the gastric wall. The inhibitory effect of vonoprazan on H+,K+-ATPase is approximately 350 times greater than that of lansoprazole, a traditional proton pump inhibitor (PPI).1Echizen H. The first-in-class potassium-competitive acid blocker, vonoprazan fumarate: pharmacokinetic and pharmacodynamic considerations.Clin Pharmacokinet. 2016; 55: 409-418Crossref PubMed Scopus (72) Google Scholar Owing to its superior efficacy, vonoprazan is expected to replace traditional PPIs. Traditional PPIs have often been linked to acute kidney injury (AKI).2Klepser D.G. Collier D.S. Cochran G.L. Proton pump inhibitors and acute kidney injury: a nested case-control study.BMC Nephrol. 2013; 14: 150Crossref PubMed Scopus (81) Google Scholar The long-term use of PPIs can lead to nephrotoxicity.3Freedberg D.E. Kim L.S. Yang Y.X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association.Gastroenterology. 2017; 152: 706-715Abstract Full Text Full Text PDF PubMed Scopus (415) Google ScholarAcute interstitial nephritis (AIN) is the main characteristic of PPI-induced AKI.4Muriithi A.K. Leung N. Valeri A.M. et al.Biopsy-proven acute interstitial nephritis, 1993-2011: a case series.Am J Kidney Dis. 2014; 64: 558-566Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar However, there have been no reports on the association between vonoprazan use and the onset of nephrotoxicity. Adverse drug reaction (ADR) reporting databases are excellent resources for postmarketing drug safety monitoring and are often used by regulatory agencies for pharmacovigilance research. Detecting safety signals using spontaneous ADR reporting databases is a well-known means for formulating hypotheses about the causal relationship between unknown or potential ADRs and drugs. We aimed to detect the safety signal for PPI- or vonoprazan-induced tubulointerstitial nephritis as the primary endpoint and that for PPI- or vonoprazan-induced AKI as the secondary endpoints using the Japanese Adverse Drug Event Report database (JADER) and clarify whether vonoprazan can induce the onset of nephrotoxicity, based on real-world data. JADER uses a report format based on the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use E2B-M2 (R3). A disproportionality analysis was conducted based on the table. The corresponding reporting odds ratio and 95% confidence interval were calculated using the known formula (see Supplementary Methods and Supplementary Tables S1 and S2). The total numbers of ADRs associated with PPIs and vonoprazan were 14,149 and 2465, respectively. Surprisingly, a safety signal for vonoprazan—a drug associated with tubulointerstitial nephritis—was detected (reporting odds ratio: 2.42; 95% confidence interval: 1.43–4.10), which was similar to that obtained for PPI as a class (Table 1). A safety signal for AKI caused by PPIs and vonoprazan was not detected.Table 1Disproportionality analysis of acute kidney injury and tubulointerstitial nephritisADRsPPI as a classVonoprazannROR95% CInROR95% CIAKI1151.0280.855–1.23670.3580.170–0.750TN1434.4413.756–5.251142.4241.432–4.103ADR, adverse drug reaction; AKI, acute kidney injury; CI, confidence interval; PPI, proton pump inhibitor; ROR, reporting odds ratio; TN, tubulointerstitial nephritis. Open table in a new tab ADR, adverse drug reaction; AKI, acute kidney injury; CI, confidence interval; PPI, proton pump inhibitor; ROR, reporting odds ratio; TN, tubulointerstitial nephritis. The time-to-onset (TTO) analysis showed that the median TTO of tubulointerstitial nephritis associated with PPIs was 41 (range: −1 to 1513) days and that associated with vonoprazan was 25 (range: 0–496) days. Similarly, the TTO of AKI associated with PPIs was 11 (range: −4 to 1628) days and that associated with vonoprazan was 10.5 (range: 5–186) days (Supplementary Figure S1). The outcomes of each ADR case are shown in Table 2. The average duration of treatment for AKI and tubulointerstitial nephritis associated with vonoprazan was 21.0 days (range: 5–51 days, n = 3) and 77.4 days (range: 0–496 days, n = 8), respectively.Table 2The outcomes after AKI and TNOutcomesaThe definitions of outcomes align with those in the ICH E2B guidelines.AKITNPPIs (n = 115)Vonoprazan (n = 7)PPIs (n = 143)Vonoprazan (n = 14)Recovered36 (31.3)3 (42.9)36 (25.2)7 (50.0)Recovering28 (24.4)1 (14.3)63 (44.0)2 (14.3)Recovered with sequelae2 (1.7)0 (0)9 (6.3)1 (7.1)Not recovered16 (13.9)0 (0)19 (13.3)2 (14.3)Death14 (12.2)1 (14.3)0 (0)0 (0)Unknown19 (16.5)2 (28.5)16 (11.2)2 (14.3)AKI, acute kidney injury; ICH, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; PPI, proton pump inhibitor; TN, tubulointerstitial nephritis.Data are presented as n (%).a The definitions of outcomes align with those in the ICH E2B guidelines. Open table in a new tab AKI, acute kidney injury; ICH, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use; PPI, proton pump inhibitor; TN, tubulointerstitial nephritis. Data are presented as n (%). In this study, we detected a safety signal for vonoprazan-induced tubulointerstitial nephritis, the primary endpoint, by disproportional analysis using the JADER database. To our knowledge, this is the first study to report the possibility of an association between vonoprazan and the onset of nephrotoxicity in the Japanese population using real-world data. For drug-induced tubulointerstitial nephritis, the causative drug becomes immunogenic via haptenization, antigen mimicry, and neoantigen formation mechanisms.5Krishnan N. Perazella M.A. Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment.Iran J Kidney Dis. 2015; 9: 3-13PubMed Google Scholar This immunologic mechanism has been hypothesized to be a cause of PPI-induced AKI, but the chemical structural formulae of vonoprazan and PPIs are completely different. The cause may not involve an immunologic mechanism, as tubulointerstitial nephritis occurs because of agents with different skeletal formulae. The mechanism of action of vonoprazan is that it competes with potassium ions for the reversible inhibition of H+-K+-ATPase, whereas PPIs act by binding covalently to the gastric H+,K+-ATPase via disulfide bonds. Thus, the mechanisms of PPI and vonoprazan action are completely different. As for PPIs, the mechanism by which vonoprazan may cause nephrotoxicity is unclear, but it is possible that tubulointerstitial nephritis may be responsible for the powerful proton pump inhibition shared commonly by PPIs and vonoprazan, thereby resulting in the common pharmacologic effect of inhibition of gastric acid secretion for a longer duration. These findings suggest that further studies are needed to confirm the associations of PPIs and vonoprazan for tubulointerstitial nephritis and investigate the underlying biological mechanisms. PPI-related nephrotoxicity is a rather rare but well-known ADR. The ADR database is useful for detecting rare but important ADRs. In this study, no safety signals for AKI (preferred term [PT] code: 10069339) caused by PPIs and vonoprazan were detected. To avoid overestimation, we chose single PTs representing AKI and AIN, except for the Standardised Medical Dictionary for Regulatory Activities/Japanese version terminology (Version 24.1) queries. Therefore, there is a possibility of missing several AKI and AIN ADR cases without PTs selected in the present study. PPIs are major causative agents of drug-induced tubulointerstitial nephritis; thus, tubulointerstitial nephritis (PT code: 10048302) could have been the appropriate selection to generate our hypothesis.5Krishnan N. Perazella M.A. Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment.Iran J Kidney Dis. 2015; 9: 3-13PubMed Google Scholar The onset of PPI-associated AIN ranged from 10 days to 18 months after treatment initiation.6Simpson I.J. Marshall M.R. Pilmore H. et al.Proton pump inhibitors and acute interstitial nephritis: report and analysis of 15 cases.Nephrology (Carlton). 2006; 11: 381-385Crossref PubMed Scopus (106) Google Scholar In the TTO analysis in the present study, the TTO findings of PPI-associated tubulointerstitial nephritis were consistent with those of previous studies. Similarly, tubulointerstitial nephritis developed at an average of 25 days after the administration of vonoprazan, but as with PPIs, the range was wide. It is necessary to monitor vonoprazan with the understanding that nephrotoxicity can occur at any time from several days to over 1 year. Regarding the outcome after nephrotoxicity, 31.3% of patients with PPI-induced AKI recovered and 24.4% were recovering; in tubulointerstitial nephritis cases, these rates were 25.2% and 44.0%, respectively. The early initiation of steroid therapy for drug-induced AIN improves kidney function to the baseline level in 54% of patients.7González E. Gutiérrez E. Galeano C. et al.Early steroid treatment improves the recovery of renal function in patients with drug-induced acute interstitial nephritis.Kidney Int. 2008; 73: 940-946Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar In the present study, more than half of the patients recovered or were recovering from AKI and tubulointerstitial nephritis after PPIs or vonoprazan treatment. Some patients discontinued PPIs or vonoprazan after the onset of tubulointerstitial nephritis. Unfortunately, JADER does not include information on steroids to resolve ADRs. Although this study was well designed and produced valuable results, it has some limitations. First, ADRs within a spontaneous reporting database are typically unvalidated or poorly validated. Second, because of the warnings from the academic societies, heightened awareness regarding acid suppressants and kidney side effects may lead to "over-reporting" of events biased against both PPIs and vonoprazan. Third, the absence of denominator means that the true odds ratios or risk ratios cannot be reported. In addition, medications associated with tubulointerstitial nephritis such as immune checkpoint inhibitors or nonsteroidal anti-inflammatory drugs as concomitant medications were prescribed in some cases; however, the information on concomitant medications in JADER was not sufficient for analysis due to the discrepancy in reporters' focus. Finally, JADER does not include information on treatment to resolve ADRs. In conclusion, in the present study, we detected a safety signal for tubulointerstitial nephritis induced by vonoprazan using a spontaneous ADR database in Japan. These findings indicate that vonoprazan might induce nephrotoxicity onset, similar to that with the use of PPIs. It is a potential safety concern; therefore, we should monitor the kidney function of all patients who are administered vonoprazan until further evidence is generated. These findings are likely to be extrapolated to other potassium-competitive acid blockers, which have the same mechanism of action, highlighting the need for additional research in this field. All the authors declared no competing interests. We would like to thank Editage (www.editage.com) for English language editing. MI, MT, JN, and HI contributed to the study conception and design. MT and YN contributed to data management. MT performed the statistical analysis. MI, MT, JN, and HI contributed to the initial draft of the manuscript and are responsible for the decision to submit the manuscript for publication. All authors contributed to data interpretation and revision of the manuscript for important content. Download .pdf (.86 MB) Help with pdf files Supplementary File (PDF)